Lipid Nanoparticle Mediated Inhibition and Detection of Matrix Metalloproteinases

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DESCRIPTION (provided by applicant): Liposomes are one of the best representatives of lipid-based nanoparticles, and they are ideally suited as the drug delivery vehicles due to their ease in formulations as well as biocompatibility. Aside from drug carriers, the liposomal nanoparticles have potentials to form template surfaces against proteins (due to intrinsic mobility of their lipid monomers), and such features can be contrived to develop highly specific diagnostic and desensitization protocols for proteins of biomedical relevance. The proposed research will develop novel liposome-based artificial antibodies , which will find applications in isozyme specific detection and inhibition of four matrix metalloproteinases (viz., MMP-2, MMP-7, MMP-9, and MMP-10), which are known to be involved in the pathogenesis of a variety of human diseases. These fundamental, process developmental , research will be accomplished under the following specific aims: (i) Synthesis of lipid conjugates to serve as the initial anchor sites for MMPs, as well as for interaction at the protein surfaces. (ii) Template polymerization of liposomes in the presence of each of the MMPs (i.e., MMP-2, -7, -9 and -10), and testing the potentials of resultant (polymerized) liposomes in isozyme selective inhibition of their parent MMPs. (iii) Isozyme-selective detection of the MMPs by employing time-resolved luminescence spectroscopy of liposome-incorporated lanthanide ions. (iv) Mechanistic studies on the roles of protein-lipid interactions in isozyme-selective detection and inhibition of MMPs. These research objectives will be accomplished by employing the techniques of synthetic organic chemistry, molecular biology, fluorescence spectroscopy, and kinetic and thermodynamic analyses of enzyme-ligand interactions and enzyme catalyses. The successful completion of this research will provide insights into developing liposomal nanoparticle-based highly specific and facile diagnostic tools for other pathogenic as well as biomarker proteins under diverse pathophysiological conditions. PUBLIC HEALTH RELEVANCE: The outcome of the proposed research will find long term applications in diagnosing and treating various cancers. During this application period, we will focus our attention in designing novel lipid nanoparticles, and in understanding the basic mechanistic principles intrinsic to the detection and inhibition of several enzymes involved in the progression and metastasis of various cancers. The successful completion of this research will establish foundation for developing diagnostic and therapeutic tools for other proteins responsible for causing different human diseases.